In 2009, Wu et al. reported on the use of the Hydration of Freeze-dried Matrix (HFDM) Method for the formation of pegylated ‘stealth’ liposomes encapsulating RNAi/siRNA, which resulted in stable particles capable of delivering RNA based therapy (RBT) to tumors, following systemic injection. However, the non-targeted nature of lipid particles stills leaves open the possibility of significant unintended side-effects in a clinical model, and limits usefulness in a basic research context. For scientific and therapeutic purposes the ability to delivery RBT directly to tumour cells, or pathologically significant cell types such as tumour vasculature has significant clinical value. Previous studies have confirmed the targeting capacity of arg-gly-aspartate (RGD) modified liposomes to target RBT to endothelial cells; however, these involve the use of lengthy, complex conjugation protocols. Here, we report on a significantly simplified protocol for the conjugation of RGD peptide to cholesterol to enable its packaging with ‘stealth’ liposomes. We further show that this targeting peptide can be used in combination with the HFDM method to produce stable particles which are effective in delivering RBT to endothelial cells in vitro; as well as tumour vasculature and tumour endothelial progenitor cells (EPCs) in vivo.